The present invention relates to E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol (I) having serum cholesterol lowering properties and to pharmaceutical compositions thereof. Compound (I) is useful in reducing serum cholesterol levels and in the treatment of atherosclerosis. It is also potentially useful in the hormone replacement therapy (HRT).
It has been demonstrated that elevated levels of serum cholesterol associated with low density lipoproteins (LDL) are a major contributing factor in the development and progression of atherosclerosis. Therefore it is desirable to provide a method for reducing serum cholesterol levels in patients with hypercholesterolemia or at risk of developing hypercholesterolemia.
International patent application WO97/32574 describes the use of Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol for lowering serum cholesterol. The compound has no significant estrogenic side effects in uterine tissue but is able to block the adverse effects of estrogen on uterus. Therefore this compound is especially useful in lowering serum cholesterol. The corresponding E-isomer is not described in this patent application.
Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol is a metabolite of known antiestrogen drug toremifene. Toremifene (Z-4-chloro-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]-phenyl]-1-butene) is currently used clinically for the treatment of estrogen receptor positive breast cancer.
Now it has been found that E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol (I) is significantly more potent in lowering serum total cholesterol but approximately equal in uterine effects when compared to the corresponding Z-isomer. This was unexpected since the E-isomer of toremifene is purely estrogenic in uterine tissue. Furthermore, it has been found that the E-isomer of the invention is able to inhibit cholesterol biosynthesis directly whereas the corresponding Z-isomer has not such effect.
Thus, E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol (I) is especially useful in lowering serum cholesterol and in the prevention or treatment of atherosclerosis. Compound (I) is also potentially useful in the hormone replacement therapy (HRT).
Accordingly, the invention provides a novel compound useful in lowering serum cholesterol levels said compound being E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and having the structure (I) 
or a pharmaceutically acceptable ester thereof.
Pharmaceutically acceptable esters include esters made with aliphatic carboxylic acids, preferably C1-6 acids, e.g. acetic acid, and made with aroma-tic carboxylic acids, e.g. C7-12 acids such as benzoic acid. The aliphatic and aromatic acids may optionally be substituted by e.g. one or more C1-4 alkyl.
The invention also provides a pharmaceutical composition comprising E-2-[4-(4-chloro1,2-diphenyl-but-1-enyl)phenoxy]ethanol or a pharmaceutically acceptable ester thereof as an active ingredient together with a pharmaceutically acceptable carrier.
The invention also provides a method of lowering serum cholesterol levels which method comprises administering to a patient in need of such treatment an effective amount of E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol or a pharmaceutically acceptable ester thereof.
The invention also provides a method for the prevention or treatment of atherosclerosis which method comprises administering to a patient in need of such treatment an effective amount of E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxylethanol or a pharmaceutically acceptable ester thereof.
The invention also provides a method of hormone replacement therapy (HRT) which method comprises administering to a patient in need of such therapy an effective amount of E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxylethanol or a pharmaceutically acceptable ester thereof.
The compound of the invention may be administered in a variety of ways including orally, parenterally or transdermally using conventional forms of preparations, such as capsules, tablets, granules, powders, suppositories, injections, patches, suspensions and syrups. The term xe2x80x9ceffective amountxe2x80x9d means an amount of compound of the invention which is capable of lowering serum total cholesterol levels or capable of blocking the adverse effects of estrogen particularly on uterus or inhibiting menopausal symptoms. The compound of the invention may be administered according to the method of the invention monthly, weekly or daily or several times a day depending upon the patient""s needs. A typical daily oral dosage is within the range of from about 0.5 mg to about 1000 mg, preferably from about 10 mg to about 800 mg, of the active compound. However, the dosage may be properly varied depending on the age, body weight and conditions of the patient as well as on the administration method. The compound of the invention may be administered alone or together with other active compounds.
The compositions according to the invention can be prepared by the methods commonly employed in the art. In addition to the active compound the compositions may contain pharmaceutically acceptable additives commonly used in the art, such as carriers, binders, excipients, lubricants, suspending agents and diluents. The amount of the active compound in the compositions of the invention is sufficient to produce the desired therapeutical effect, for example about 0.5 to 1000 mg, preferably about 10 mg to 800 mg, in unit dosage for both oral and parenteral administration.